Medullary cystic kidney disease (MCKD) type 1 is a rare disorder characterized by autosomal dominant inheritance of tubulo-interstitial kidney disease (Bleyer et al., 2010, Semin. Nephrol 30, 366-373). Affected individuals develop a slow deterioration in kidney function (specifically, in glomerular filtration rate), usually commencing in the second to third decade of life and resulting in the need for dialysis or kidney transplantation approximately two decades later. Diagnosis of MCKD1 in patients is complicated by the disease's variable severity and age at onset, its absence of extrarenal manifestations, and its absence of characteristic renal manifestations such as hematuria, proteinuria, nephrolithiasis, or pathognomonic morphological changes in the kidney. These characteristics, together with the high frequency of kidney disease in the general population (Castro et al., 2009, Am. J. Kidney Dis. 53, S46-S55), have complicated individual diagnosis and have hampered MCKD1 research. Diagnostic difficulties have also prevented living related kidney donation, as potential donor family members have not known their status as unaffected or (yet-to-be) affected. Conclusive determination of the molecular bases of MCKD1 would lead both to much-needed diagnostics for families and to general functional insights into the pathogenesis of tubulo-interstitial kidney disease, which could inform prevention and therapy.
Despite these potential challenges, MCKD1 has been compellingly and consistently mapped to a single autosomal locus at 1q21. First linked in a large Cypriot population in 1998 (Christodoulou, K. et al., 1998, Hum. Mol. Genet. 119, 649-658), linkage to 1q21 has also been reported in several families from Finland (Auranen et al., 2001, Kidney Int. 60, 1225-1232), Saudia Arabia (Al-Romaih, K. I., et al., 2011, Am. J. Kidney Dis. 58, 186-195), a Native-American kindred (Kiser, R. L. et al, 2004, Am. J. Kidney Dis., 44, 611-617), many additional families of European descent (Wolf, M. T. F. et al, 2006, Hum. Genet. 7, 905-911; Fuchshuber, A. et al., 2001, Genomics, 72, 278-284), and a family with co-existing bipolar disease. Attempts to identify the mutated gene(s), however, have not been successful; mutational analysis of 37 candidate genes within the linked interval in 23 MCKD1 patients was unable to identify the causative genetic mutation(s) (Wolf, M. T. F. et al, 2006, Hum. Genet. 7, 905-911).
The advent of massively parallel sequencing (MPS) technologies has made exhaustive sequencing of genomic regions a viable approach to the identification of genes responsible for rare Mendelian diseases caused by high penetrance mutations. Yet, there is also a growing recognition that using MPS to discover disease genes is not always straightforward.
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